PROJECT SUMMARY There is a fundamental gap in the availability of cognitive outcome measures that are reliable and sensitive to detecting change among children with Down syndrome (DS). Lack of such outcome measures represents an important problem to interpreting clinical trials aimed at improving the lives of individuals with DS. Without evidence-based cognitive outcome measures, future treatment trials in this population will remain suboptimal due to poor study measures. Despite some promising findings in currently recommended assessment batteries, the evidence base for cognitive outcome measures in DS is limited. Multi-site studies evaluating the reliability and validity of outcome measures are the needed next step towards supporting the evaluation of new pharmaceutical and clinical interventions for children with DS. Working groups convened by NICHD of leading experts in DS led to recommendations of promising measures for use in this population. The current study proposes to evaluate the psychometric properties of recommended promising measures and expands upon these recommendations by evaluating individual variability and accounting for the method of assessment (verbal, nonverbal, computer, parent-report) to support our understanding of performance within a cognitive domain. The overall objective of this application is to establish the psychometric properties of clinical outcome measures in children with DS across the cognitive domains of executive functioning (inhibition, working memory, set-shifting), learning and memory, and processing speed. Our rationale for working with this population is that DS is associated with a distinct pattern of cognitive strengths and weaknesses related to their neuroanatomy. Thus the selection of outcome measures to be evaluated needs to take into account the DS behavioral phenotype. We propose three specific aims: 1) To examine the psychometric properties of measures in the assessment battery with children with DS. 2) To evaluate differences in the psychometric properties of the measures as a function of variations in demographics and medical comorbidities. 3) To characterize the developmental trajectories of cognition and executive functioning. To achieve these aims, 160 children ages 6-17 years with DS will participate in repeated neuropsychological assessments with follow-up evaluations at 2 weeks, 3 months, 6 months, and 1 year. Parents and teachers will complete ratings of executive functioning, adaptive behavior and behavioral concerns. Our research team is uniquely positioned to conduct this work, combining expertise in DS, neuropsychological assessment, medical conditions and measurement evaluation. We anticipate that this measurement study will provide critical guidance for future efficacy and effectiveness trials. Our goals are in line with NICHD PAR-16-216 research priority to assess the reliability, validity and change over time of measures for use in clinical trials in ID, in this case specifically targeted to DS. As our field continues to develop new pharmaceutical and clinical interventions, our project will support this work and have an impact on the 400,000 individuals with DS living in the United States.